Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome

Abstract

To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by ∼7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. Neurons, particularly in these brain regions, had aberrant mitochondrial morphology. Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.cerebellum | mitochondria | gliosis | neurodegeneration | vestibular nucleus

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

“…Importantly, whereas cardiac muscle has a high energy requirement and is dependent on OXPHOS for normal function, the cardiac specificity of the Ndufs6 gt/gt phenotype is unlikely to be due simply to high reliance on CI activity or different energy substrate preferences in heart. In a mouse model of systemic CI deficiency (i.e., Ndufs4 −/− mice), animals die from neurological disease without overt heart disease (16,17).…”

“…Ndufs4 knockout mice develop encephalomyopathy and die within 7 wk (16). A brain-specific Ndufs4 knockout showed a nearly identical phenotype to the systemic knockout with death by 7 wk (17). These are useful models but do not develop the characteristic neuropathology of Leigh syndrome and the early lethality means they can only be used in short-term treatment studies.…”

Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome

“…Ndufs4 assists in the final stages of complex I assembly, and its absence results in the formation of a smaller ϳ830 kDa subcomplex that lacks the NADH dehydrogenase module and has significantly less electron shuttling activity than the intact holoenzyme (24,25). Ndufs4 mutations are associated with brainstem deterioration in humans (26), and a recently described Ndufs4 knockout mouse (Ndufs4 KO) exhibits many of the clinical and neurological symptoms observed in human Leigh syndrome (27,28).One of the most common clinical features of MD is lactic acidosis, derived from the accumulation of pyruvate and elevated NADH. Increased lactate or lactate:pyruvate ratios have been measured in the blood, urine, and cerebrospinal fluid of a large number of Leigh syndrome patients (15,16).…”

“…Ndufs4 assists in the final stages of complex I assembly, and its absence results in the formation of a smaller ϳ830 kDa subcomplex that lacks the NADH dehydrogenase module and has significantly less electron shuttling activity than the intact holoenzyme (24,25). Ndufs4 mutations are associated with brainstem deterioration in humans (26), and a recently described Ndufs4 knockout mouse (Ndufs4 KO) exhibits many of the clinical and neurological symptoms observed in human Leigh syndrome (27,28).…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…For disorders where the pathogenesis originates from mutations in nuclear genes whose encoded products participate in OXPHOS, standard methodologies for nuclear transgenesis can be used. A recent example is a transgenic model of Leigh syndrome, which is caused by mutations in the gene encoding NADH dehydrogenase (ubiquinone) iron-sulfur protein 4 (NDUFS4), a nuclear-encoded complex I subunit [48]. Transgenic mice with a conditional knockout of the NDUFS4 gene presented with a fatal progressive encephalopathy similar to human patients, regardless of whether the knockout was global or exclusive to the central nervous system (CNS), suggesting that NDUFS4 function is of particular relevance to the CNS.…”